tbuckley/cabot-search huggingface dataset:
Integrative Analysis of Proteomics and Transcriptomics Reveals Endothelin Receptor B as Novel Single Target and Identifies New Combinatorial Targets for Multiple Myeloma
Authors: Margaux Lejeune, Murat Cem Köse, Mégane Jassin, Marie-Jia Gou, Amaury Herbet, Elodie Duray, Gaël Cobraiville, Jacques Foguenne, Didier Boquet, André Gothot, Yves Beguin, Marianne Fillet, Jo Caers
Journal: HemaSphere (2023)

Despite the recent introduction of next-generation immunotherapeutic agents, multiple myeloma (MM) remains incurable. New strategies targeting MM-specific antigens may result in a more effective therapy by preventing antigen escape, clonal evolution, and tumor resistance. In this work, we adapted an algorithm that integrates proteomic and transcriptomic results of myeloma cells to identify new antigens and possible antigen combinations. We performed cell surface proteomics on 6 myeloma cell lines based and combined these results with gene expression studies. Our algorithm identified 209 overexpressed surface proteins from which 23 proteins could be selected for combinatorial pairing. Flow cytometry analysis of 20 primary samples confirmed the expression of FCRL5, BCMA, and ICAM2 in all samples and IL6R, endothelin receptor B (ETB), and SLCO5A1 in >60% of myeloma cases. Analyzing possible combinations, we found 6 combinatorial pairs that can target myeloma cells and avoid toxicity on other organs. In addition, our studies identified ETB as a tumor-associated antigen that is overexpressed on myeloma cells. This antigen can be targeted with a new monoclonal antibody RB49 that recognizes an epitope located in a region that becomes highly accessible after activation of ETB by its ligand. In conclusion, our algorithm identified several candidate antigens that can be used for either single-antigen targeting approaches or for combinatorial targeting in new immunotherapeutic approaches in MM.
Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia
Authors: Caner Saygin, Giorgia Giordano, Kathryn Shimamoto, Bart Eisfelder, Anika Thomas-Toth, Girish Venkataraman, Vijayalakshmi Ananthanarayanan, Tiffaney L. Vincent, Adam DuVall, Anand A. Patel, Yi Chen, Fenlai Tan, Stephen P. Anthony, Yu Chen, Yue Shen, Olatoyosi Odenike, David T. Teachey, Barbara L. Kee, James LaBelle, Wendy Stock
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Relapsed T-acute lymphoblastic leukemia (T-ALL) has limited treatment options. We investigated mechanisms of resistance to BH3 mimetics in T-ALL to develop rational combination strategies. We also looked at the preclinical efficacy of NWP-0476, a novel BCL-2/BCL-xL inhibitor, as single agent and combination therapy in T-ALL. Experimental Design: We used BH3 profiling as a predictive tool for BH3 mimetic response in T-ALL. Using isogenic control, venetoclax-resistant (ven-R) and NWP-0476-resistant (NWP-R) cells, phosphokinase array was performed to identify differentially regulated signaling pathways. Results: Typical T-ALL cells had increased dependence on BCL-xL, whereas early T-precursor (ETP)-ALL cells had higher BCL-2 dependence for survival. BCL-2/BCL-xL dual inhibitors were effective against both subtypes of T-lineage ALL. A 71-protein human phosphokinase array showed increased LCK activity in ven-R cells, and increased ACK1 activity in ven-R and NWP-R cells. We hypothesized that pre-TCR and ACK1 signaling pathways are drivers of resistance to BCL-2 and BCL-xL inhibition, respectively. First, we silenced LCK gene in T-ALL cell lines, which resulted in increased sensitivity to BCL-2 inhibition. Mechanistically, LCK activated NF-κB pathway and the expression of BCL-xL. Silencing ACK1 gene resulted in increased sensitivity to both BCL-2 and BCL-xL inhibitors. ACK1 signaling upregulated AKT pathway, which inhibited the pro-apoptotic function of BAD. In a T-ALL patient-derived xenograft model, combination of NWP-0476 and dasatinib demonstrated synergy without major organ toxicity. Conclusions: LCK and ACK1 signaling pathways are critical regulators of BH3 mimetic resistance in T-ALL. Combination of BH3 mimetics with tyrosine kinase inhibitors might be effective against relapsed T-ALL.
Safety and activity of the first-in-class locked nucleic acid (LNA) miR-221 selective inhibitor in refractory advanced cancer patients: a first-in-human, phase 1, open-label, dose-escalation study
Authors: Pierfrancesco Tassone, Maria Teresa Di Martino, Mariamena Arbitrio, Lucia Fiorillo, Nicoletta Staropoli, Domenico Ciliberto, Alessia Cordua, Francesca Scionti, Bernardo Bertucci, Angela Salvino, Mariangela Lopreiato, Fredrik Thunarf, Onofrio Cuomo, Maria Cristina Zito, Maria Rosanna De Fina, Amelia Brescia, Simona Gualtieri, Caterina Riillo, Francesco Manti, Daniele Caracciolo, Vito Barbieri, Eugenio Donato Di Paola, Adele Emanuela Di Francesco, Pierosandro Tagliaferri
Journal: Journal of Hematology & Oncology (2023)

Abstract Background We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation. Methods In this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0–2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33). Results Seventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3–4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose. Conclusions The excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898).
A Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor
Authors: Suzanne George, Michael C. Heinrich, Neeta Somaiah, Peter Oppelt, Robert McLeod, Satoshi Nishioka, Madan G. Kundu, Xiaozhong Qian, Prasanna Kumar, Abderrahmane Laadem, Yvonne Lau, Brittany P. Tran, Maura Fallon, Ololade Dosunmu, Julia Shi, Yoichi Naito
Journal: Clinical Cancer Research (2023)

Abstract Purpose: To evaluate DS-6157a, an antibody–drug conjugate targeting G protein–coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST). Patients and Methods: In this phase I multicenter, open-label, multiple-dose study, patients with previously treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg. The primary objective evaluated the safety and tolerability of DS-6157a, while determining dose-limiting toxicity (DLT) and the MTD. Secondary objectives included plasma pharmacokinetics parameters, plasma antidrug antibodies (ADA), and efficacy. Results: A total of 34 patients enrolled. DS-6157a was well tolerated, with DLTs in 4 patients (11.8%) at doses of 6.4 mg/kg, 9.6 mg/kg, and 12.8 mg/kg; the MTD was determined to be 6.4 mg/kg. Treatment-emergent adverse events (TEAE) grade ≥3 occurred in 17 patients (50.0%), including decreased platelet count (23.5%), anemia (20.6%), decreased neutrophil count (14.7%), and decreased white blood cell count (11.8%). Four patients (11.8%) experienced serious adverse events related to DS-6157a. Six patients died with 5 due to disease progression and 1 due to DS-6157a-related TEAE. Tumor shrinkage was observed in 7 patients (20.6%), and 1 patient (2.9%) achieved a partial response. Plasma concentrations and exposure of intact DS-6157a, DXd, and total anti-GPR20 antibody all demonstrated a dose-dependent profile. No treatment-emergent ADAs were observed. Conclusions: Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild-type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.
Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study
Authors: Ana Oaknin, Bhavana Pothuri, Lucy Gilbert, Renaud Sabatier, Jubilee Brown, Sharad Ghamande, Cara Mathews, David M. O'Malley, Rebecca Kristeleit, Valentina Boni, Adriano Gravina, Susana Banerjee, Rowan Miller, Joanna Pikiel, Mansoor R. Mirza, Ninad Dewal, Grace Antony, Yuping Dong, Eleftherios Zografos, Jennifer Veneris, Anna V. Tinker
Journal: Clinical Cancer Research (2023)

Abstract Purpose: This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators. Patients and Methods: A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for four cycles, then 1,000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR). Results: A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports. Conclusions: Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab. See related commentary by Jangra and Dhani, p. 4521
Reconstructing avascular necrotic femoral head through a bioactive β-TCP system: From design to application
Authors: Yajie Lu, Xiantao Chen, Xiao Lu, Changning Sun, Minghui Li, Guojing Chen, Zuoyao Long, Yuan Gao, Haoqiang Zhang, Mengquan Huang, Chuanlei Ji, Hongbin Fan, Dong Liu, Yuewen Hao, Hong Wang, Leilei Zhang, Hongmei Zhang, Jianxi Lu, Zhen Wang, Jing Li
Journal: Bioactive Materials (2023)

A variety of techniques have been used for treating avascular necrosis of the femoral head (ANFH), but have frequently failed. In this study, we proposed a β-TCP system for the treatment of ANFH by boosting revascularization and bone regeneration. The angio-conductive properties and concurrent osteogenesis of the highly interconnected porous β-TCP scaffold were revealed and quantified through an in vivo model that simulated the ischemic environment of ANFH. Mechanical test and finite element analysis showed that the mechanical loss caused by tissue necrosis and surgery was immediately partially compensated after implantation, and the strength of the operated femoral head was adaptively increased and eventually returned to normal bone, along with continuous material degradation and bone regeneration. For translational application, we further conducted a multi-center open-label clinical trial to assess the efficacy of the β-TCP system in treating ANFH. Two hundred fourteen patients with 246 hips were enrolled for evaluation, and 82.1% of the operated hips survived at a 42.79-month median follow-up. The imaging results, hip function, and pain scores were dramatically improved compared to preoperative levels. ARCO stage Ⅱ disease outperformed stage Ⅲ in terms of clinical effectiveness. Thus, bio-adaptive reconstruction using the β-TCP system is a promising hip-preserving strategy for the treatment of ANFH.
Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer
Authors: Luigi Perelli, Federica Carbone, Li Zhang, Justin K. Huang, Courtney Le, Hania Khan, Francesca Citron, Edoardo Del Poggetto, Tony Gutschner, Hideo Tomihara, Melinda Soeung, Rosalba Minelli, Sanjana Srinivasan, Michael Peoples, Truong Nguyen Anh Lam, Sebastian Lundgren, Ruohan Xia, Cihui Zhu, Alaa M. T. Mohamed, Jianhua Zhang, Kanishka Sircar, Alessandro Sgambato, JianJun Gao, Eric Jonasch, Giulio F. Draetta, Andrew Futreal, Ziad Bakouny, Eliezer M. Van Allen, Toni Choueiri, Sabina Signoretti, Pavlos Msaouel, Kevin Litchfield, Samra Turajlic, Linghua Wang, Ying Bei Chen, Renzo G. Di Natale, A. Ari Hakimi, Virginia Giuliani, Timothy P. Heffernan, Andrea Viale, Christopher A. Bristow, Nizar M. Tannir, Alessandro Carugo, Giannicola Genovese
Journal: Nature Cancer (2023)

Abstract Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR–Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect of the interferon receptor genes cluster as an adaptive mechanism to deleterious chromosomal instability in metastatic progression. This work provides critical knowledge on drivers of renal cell carcinoma progression and defines the primary role of interferon signaling in constraining the propagation of aneuploid clones in cancer evolution.
TIGIT is a key inhibitory checkpoint receptor in lymphoma
Authors: James Godfrey, Xiufen Chen, Nicole Sunseri, Alan Cooper, Jovian Yu, Arina Varlamova, Dmitry Zarubin, Yuriy Popov, Connor Jacobson, Ekaterina Postovalova, Zhongmin Xiang, Krystle Nomie, Aleksander Bagaev, Girish Venkataraman, Yuanyuan Zha, Sravya Tumuluru, Sonali M Smith, Justin P Kline
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background PD-1 checkpoint blockade therapy (CBT) has greatly benefited patients with select solid tumors and lymphomas but has limited efficacy against diffuse large B-cell lymphoma (DLBCL). Because numerous inhibitory checkpoint receptors have been implicated in driving tumor-specific T cell dysfunction, we hypothesized that combinatorial CBT would enhance the activity of anti-PD-1-based therapy in DLBCL. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a coinhibitory receptor expressed on dysfunctional tumor-infiltrating T cells, and TIGIT blockade has demonstrated encouraging activity in combination with PD-1 blockade in murine tumor models and in clinical studies. However, the degree to which TIGIT mediates T cell dysfunction in DLBCL has not been fully explored. Results Here, we demonstrate that TIGIT is broadly expressed on lymphoma-infiltrating T cells (LITs) across a variety of human lymphomas and is frequently coexpressed with PD-1. TIGIT expression is particularly common on LITs in DLBCL, where TIGIT + LITs often form distinct cellular communities and exhibit significant contact with malignant B cells. TIGIT + /PD-1 + LITs from human DLBCL and murine lymphomas exhibit hypofunctional cytokine production on ex vivo restimulation. In mice with established, syngeneic A20 B-cell lymphomas, TIGIT or PD-1 mono-blockade leads to modest delays in tumor outgrowth, whereas PD-1 and TIGIT co-blockade results in complete rejection of A20 lymphomas in most mice and significantly prolongs survival compared with mice treated with monoblockade therapy. Conclusions These results provide rationale for clinical investigation of TIGIT and PD-1 blockade in lymphomas, including DLBCL.
Caloric reductions needed to achieve obesity goals in Mexico for 2030 and 2040: A modeling study
Authors: Francisco Reyes-Sánchez, Ana Basto-Abreu, Rossana Torres-Álvarez, Martha Carnalla-Cortés, Alan Reyes-García, Boyd Swinburn, Rafael Meza, Juan A. Rivera, Barry Popkin, Tonatiuh Barientos-Gutiérrez
Journal: PLoS Medicine (2023)

In Mexico, obesity prevalence among adults increased from 23% in 2000 to 36% in 2018, approximately. Mexico has not defined short- or long-term obesity goals, obscuring the level of effort required to achieve a relevant impact. We aimed to explore potential obesity goals for 2030 and 2040 in Mexico and to estimate the required caloric reductions to achieve them.We obtained anthropometric and demographic information on the Mexican adult population (age ≥20 years) from the Health and Nutrition Surveys conducted in 2000, 2006, 2012, 2016, and 2018 (n = 137,907). Each survey wave is cross-sectional, multistage, and representative of the Mexican population at the national, regional, and urban/rural levels. Obesity prevalence was projected for 2030 and 2040 by combining population projections of energy intake by socioeconomic status (SES) with a weight-change microsimulation model taking into account individual-level information on sex, age, physical activity, and initial body weight and height. If current trends continue, Mexico's obesity prevalence is expected to increase from 36% (95% CI 35% to 37%) in 2018 to 45% (uncertainty interval [UI] 41% to 48%) in 2030 and to 48% (UI 41% to 55%) in 2040. Based on expert opinion, we identified 3 obesity goals scenarios: (1) plausible (38% in 2030 and 36% in 2040); (2) intermediate (33% in 2030 and 29% in 2040); and (3) ideal based on the average prevalence of Organization for Economic Co-operation and Development countries (OECD; 19%). We estimated the caloric reductions needed to achieve the goal scenarios using the microsimulation model. Obesity was projected to increase more rapidly in the low SES (around 34% in 2018 to 48% (UI 41% to 55%) in 2040), than in the middle (around 38% to 52% (UI 45% to 56%)), or high SES group (around 36% to 45% (UI 36% to 54%)). Caloric reductions of 40 (UI 13 to 60), 75 (UI 49 to 95), and 190 (UI 163 to 215) kcal/person/day would be needed to reach the plausible, intermediate, and the ideal (OECD) average scenarios for 2030, respectively. To reach the 2040 goals, caloric reductions of 74 (UI 28 to 114), 124 (UI 78 to 169), and 209 (UI 163 to 254) kcal/person/day would be required, respectively. Study limitations include assuming a constant and sedentary physical activity level, not considering cohort-specific differences that could occur in the future, and assuming the same caloric trends under no intervention and the obesity goal scenarios.To reach the 3 obesity goals in 2040, caloric reductions between 74 and 209 kcal/day/person would be needed in Mexico. A package of new and stronger interventions should be added to existing efforts such as food taxes and warning labels on non-nutritious food.
CLDN18.2 and 4-1BB bispecific antibody givastomig exerts antitumor activity through CLDN18.2-expressing tumor-directed T-cell activation
Authors: Jing Gao, Zhengyi Wang, Wenqing Jiang, Yanni Zhang, Zhen Meng, Yanling Niu, Zhen Sheng, Chan Chen, Xuejun Liu, Xi Chen, Chanjuan Liu, Keren Jia, Cheng Zhang, Haiyan Liao, Jaeho Jung, Eunsil Sung, Hyejin Chung, Jingwu Z. Zhang, Andrew X. Zhu, Lin Shen
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Claudin18.2 (CLDN18.2) is a tight junction protein that has been identified as a clinically proven target in gastric cancer. Stimulation of 4-1BB with agonistic antibodies is also a promising strategy for immunotherapy and 4-1BB + T cells were reported to be present within the tumor microenvironment of patients with gastric cancer. However, hepatotoxicity-mediated by 4-1BB activation was observed in clinical trials of agonistic anti-4-1BB monoclonal antibodies. Methods To specifically activate the 4-1BB + T cells in tumor and avoid the on-target liver toxicity, we developed a novel CLDN18.2×4-1BB bispecific antibody (termed ‘givastomig’ or ‘ABL111’; also known as TJ-CD4B or TJ033721) that was designed to activate 4-1BB signaling in a CLDN18.2 engagement-dependent manner. Results 4-1BB + T cells were observed to be coexisted with CLDN18.2 + tumor cells in proximity by multiplex immunohistochemical staining of tumor tissues from patients with gastric cancer (n=60). Givastomig/ABL111 could bind to cell lines expressing various levels of CLDN18.2 with a high affinity and induce 4-1BB activation in vitro only in the context of CLDN18.2 binding. The magnitude of T-cell activation by givastomig/ABL111 treatment was closely correlated with the CLDN18.2 expression level of tumor cells from gastric cancer patient-derived xenograft model. Mechanistically, givastomig/ABL111 treatment could upregulate the expression of a panel of pro-inflammatory and interferon-γ-responsive genes in human peripheral blood mononuclear cells when co-cultured with CLDN18.2 + tumor cells. Furthermore, in humanized 4-1BB transgenic mice inoculated with human CLDN18.2-expressing tumor cells, givastomig/ABL111 induced a localized immune activation in tumor as evident by the increased ratio of CD8 + /regulatory T cell, leading to the superior antitumor activity and long-lasting memory response against tumor rechallenge. Givastomig/ABL111 was well tolerated, with no systemic immune response and hepatotoxicity in monkeys. Conclusions Givastomig/ABL111 is a novel CLDN18.2×4-1BB bispecific antibody which has the potential to treat patients with gastric cancer with a wide range of CLDN18.2 expression level through the restricted activation of 4-1BB + T cells in tumor microenvironment to avoid the risk of liver toxicity and systemic immune response.